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Infection and Immunity, September 2004, p. 5373-5382, Vol. 72, No. 9
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.9.5373-5382.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Involvement of CD14, Toll-Like Receptors 2 and 4, and MyD88 in the Host Response to the Fungal Pathogen Cryptococcus neoformans In Vivo

Lauren E. Yauch,1 Michael K. Mansour,1 Shmuel Shoham,1,{dagger} James B. Rottman,2 and Stuart M. Levitz1*

Departments of Medicine and Microbiology, Boston University School of Medicine, Boston,1 Archemix Corporation, Cambridge, Massachusetts2

Received 3 May 2004/ Returned for modification 2 June 2004/ Accepted 16 June 2004

The major capsular polysaccharide of Cryptococcus neoformans, glucuronoxylomannan (GXM), is recognized by Toll-like receptor 2 (TLR2), TLR4, and CD14. In these studies, mice deficient in CD14, TLR2, TLR4, and the TLR-associated adaptor protein, MyD88, were utilized to investigate the contribution of TLRs and CD14 to in vivo host defenses against C. neoformans. MyD88–/– mice had significantly reduced survival compared with wild-type C57BL/6 mice after intranasal (i.n.) and intravenous (i.v.) infection with live C. neoformans. CD14–/– mice had reduced survival when infected i.v., while TLR2–/– mice died significantly earlier after i.n. infection. Mortality was similar comparing TLR4 mutant C3H/HeJ mice and control C3H/HeOuJ mice following i.v. or i.n. challenge with C. neoformans. The course of pulmonary cryptococcosis was studied in more detail in the CD14–/–, TLR2–/–, and MyD88–/– mice. MyD88–/– mice infected i.n. had higher numbers of CFU in the lungs as well as higher GXM levels in the sera and lungs 7 days after infection than wild-type mice did. Surprisingly, there were no major differences in the levels of tumor necrosis factor alpha, interleukin-4 (IL-4), IL-10, IL-12p70, or gamma interferon in the lungs of C. neoformans-infected knockout mice compared with wild-type mice. Histopathologic analysis of the lungs on day 7 postinfection revealed minimal inflammation in all mouse groups. These studies demonstrate a major role for MyD88 and relatively minor roles for CD14 and TLR2 in the response to cryptococcal infection, with the decreased survival of MyD88–/– mice correlating with increased numbers of lung CFU and serum and lung GXM levels.

* Corresponding author. Mailing address: Section of Infectious Diseases, 650 Albany St., Boston University Medical Center, Boston, MA 02118. Phone: (617) 638-7904. Fax: (617) 638-7923. E-mail: slevitz{at}bu.edu.

Editor: T. R. Kozel

{dagger} Present address: Section of Infectious Diseases, Washington Hospital Center, Washington, D.C.

Infection and Immunity, September 2004, p. 5373-5382, Vol. 72, No. 9
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.9.5373-5382.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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